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July 25, 2013

Novozymes A/S v. DuPont Nutrition Biosciences APS (Fed. Cir. 2013)

It
has long been a practice in prosecuting a patent application to keep a
continuation application pending during the term of any granted patent. This practice is advantageous because it
permits the patentee to pursue specific claims in a later-filed application to
a competitor's product that falls within the scope of the invention as
disclosed in the specification. Of
course, this strategy requires that later-filed claims be disclosed in the
specification as originally filed to satisfy the enablement and written
description requirements of 35 U.S.C. § 112. In re Ruschig, 379 F.2d 990 (CCPA
1967).

These
considerations arose in the Federal Circuit's decision in Novozymes v. DuPont Nutrition Biosciences in a patent infringement
lawsuit involving modified alpha-amylase enzymes. Alpha-amylases are enzymes produced in
microorganisms and higher plants and animals (including man) that catalyze the
breakdown of certain polysaccharides. The enzymes are used commercially, inter
alia, in detergents, sugar refining, and ethanol production, but as enzymes
are sensitive to elevated temperatures and pH extremes. Novozymes' commercial embodiment of this
enzyme is obtained from Bacillus
licheniformis (BLA) and sold as Termamyl™.

Traditionally,
alpha-amylases are stabilized against the deleterious effects of heat and
extreme pH by complexing with calcium, which "represents an added cost and
often imposes undesirable effects on industrial equipment." In an effort to avoid these costs and
undesirable effects, Novozymes "pursued two parallel strategies in attempting to identify promising mutation sites among the approximately 500 amino
acids that make up a Bacillus alpha-amylase polypeptide: rational
protein design [which attempted to use knowledge and information on the effects
of mutations in amino acid sequence on protein structure] and random
mutagenesis [which did not]." The
priority application of the patent-in-suit at issue in this case disclosed 17
amino acid sequence positions identified by rational design and 16 positions
identified by random mutagenesis that were candidates for amino acid changing
mutations in two bacterial alpha-amylases: the B. licheniformis species that comprised the company's Termamyl™ product
and a species from B. stearothermophilus
("BSG"), as well as five other bacterial alpha-amylase species. As disclosed in the specification of the
priority document, these changes could involve substitution of the amino acid
at each of these 33 positions with one of the other 19 naturally occurring
amino acids, or could involve deletion of the amino acid at that position (a
total of 20 possible changes for each of the 33 candidate positions). Accordingly, the total number of variant B. licheniformis species disclosed
generically in the priority document amounted to about 8.6 x 1042. In fact, the specification of the priority
document provided but two specific examples with actual experimental data. However, many of the substitutions were
found not to provide variant alpha-amylase enzymes having "improved
stability at 'high temperatures (i.e., 70-120°C.) and/or extreme pH (i.e., low
or high pH, i.e., pH 4-6 or pH 8-11), in particular at free (i.e., unbound,
therefore in solution) calcium concentrations below 60 ppm.'"

DuPont's
accused product was a B.
stearotherophilus variant species having an amino acid sequence change at
position 239 from a serine to a glutamic acid (abbreviated "S239Q"). As noted in the Federal Circuit opinion, "DuPont
produced approximately 1,500 alpha-amylase variants with substitutions covering
150 of the 515 amino acid positions in the parent BSG enzyme. . . . DuPont then
screened its panel of 1,500 variants for increased thermostability under
low-calcium conditions and identified a variant substituted at position 239 [the
S239Q variant] as the best performer."

In
response, Novozymes filed a continuation application that resulted in the patent-in-suit,
U.S. Patent No. 7,713,723; claim 1 is representative:

1. An isolated variant of a parent
alpha-amylase, wherein: (a)
the variant has at least 90% sequence identity to SEQ ID NO: 6 [BSG
alpha-amylase], (b)
the variant comprises a substitution of serine at position 239 relative
to the parent alpha- amylase, using the amino acid sequence of SEQ ID NO: 8
[BLA alpha-amylase] for determining position numbering, and (c)
the variant has increased thermostability relative to the parent alpha-amylase,
wherein thermostability is determined at pH 4.5, 90° C. and 5 ppm calcium and
has alpha-amylase activity

(emphasis in opinion).

The District Court granted summary judgment of infringement against DuPont and denied
DuPont's summary judgment motion of invalidity under 35 U.S.C. § 112
for failure to satisfy the written description requirement, based on there
being disputed issues of fact. (The Court also denied Novozymes' preliminary injunction motion on the grounds that
there was considerable question of whether Novozymes would prevail on the
merits in view of DuPont's invalidity challenge.) The Court submitted to the jury the question of
whether the claims were invalid under 35 U.S.C. § 112
for failure to satisfy the enablement or written description requirements, and
the jury found (using a special verdict form) that the claims were not invalid,
awarding Novozymes a judgment of more than $18 million. The Court granted DuPont's JMOL motion, on
the grounds that the specification did not provide an adequate written
description of the invention as claimed, relying on both Federal Circuit and
CCPA precedent including Boston Scientific Corp. v. Johnson & Johnson, 647 F.3d 1353 (Fed. Cir. 2011);
Billups-Rothenberg, 642 F.3d 1031, 1036 (Fed. Cir. 2011); Centocor
Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341 (Fed. Cir. 2011); Univ.
of Rochester v. G.D. Searle & Co., 358 F.3d 916 (Fed. Cir. 2004); Purdue
Pharma L.P. v. Faulding Inc., 230 F.3d 1320 (Fed. Cir. 2000); In re
Ruschig, 379 F.2d 990 (CCPA 1967).

The
Federal Circuit affirmed, in an opinion by Judge Schall joined by Judge Bryson,
with Chief Judge Rader dissenting. The
majority opinion rejected Novozymes' contentions that any deficiencies in the
disclosure in its specification was ameliorated by the general understanding,
knowledge and skill in the art, citing Snitzer v. Etzel, 465 F.2d 899
(CCPA 1972), and Union Oil Co. of California v. Atlantic Richfield Co.,
208 F.3d 989 (Fed. Cir. 2000). DuPont,
in contrast, relied on In re Ruschig,
arguing successfully that Novozymes' disclosure amounted to nothing more than
an "invitation to experiment," and unsuccessfully at that, pointing
out that Novozymes' "application fails to disclose a single alpha- amylase
variant substituted at position 239 that actually exhibits increased
thermostability, noting that the only disclosed substitution at that position
(S239W) disclosed in the '723 priority application does not work as required by the '723
patent's claims."

The
majority stated its holding expressly: "no reasonable jury could find that
the claims of the '723 patent meet the written description requirement of §
112, ¶ 1, and that the district court therefore correctly entered judgment as a
matter of law invalidating those claims." The opinion contrasts the specificity of the claims with the generic
disclosure of the specification, noting that Novozymes provided only "generalized
guidance listing several variables that might, in some combination, lead to a
useful result." This determination
was mandated by "[n]umerous prior decisions" from both the CCPA and
the Federal Circuit, citing most of the canonical precedent including In re
Ruschig, Boston Scientific Corp. v. Johnson & Johnson, and Univ.
of Rochester v. G.D. Searle & Co., and distinguishing Snitzer v.
Etzel and Union Oil Co. of California v. Atlantic Richfield Co. In
the Snitzer case, the majority noted
that the specification of the patent at issue provided disclosure of a small number of distinctly recited species,
in stark contrast to the overwhelming number of species falling within the
ambit of the '723 patent specification, while in the Union Oil case the specification "defined the claimed gasoline
compositions in terms of various chemical and physical properties" and
that "ordinarily skilled petroleum refiners would immediately appreciate
that the qualitative chemical properties recited in the claims translated to
specific, manifest compositions that would yield those properties."

The majority expressly found that the '723
specification, and the disclosure of the priority document, "contains no
disclosure of any variant that actually satisfies the claims, nor is there
anything to suggest that Novozymes actually possessed such a variant at the
time of filing." While the opinion
recognizes distinctions between Novozymes' specification and the deficiencies
in the specifications in the authorities it cites to support their opinion, "[o]n
closer inspection these 'analogies fall flat.'" "Taking each claim -- as we must -- as an
integrated whole rather than as a collection of independent limitations, one
searches the ['723 priority] application in vain for the disclosure of even a
single species that falls within the claims or for any 'blaze marks' that would
lead an ordinarily skilled investigator toward such a species among a slew of
competing possibilities," according to the opinion, and "working
backwards" from the claims (and the accused product) impermissibly "seeks
to derive written description support from an amalgam of disclosures plucked
selectively from the '723 priority application." Even Novozymes' expert agreed with DuPont that "one could not know
which, if any, individual substitutions at any of the seventeen sites selected
by rational protein design would yield increased thermostability without
actually making and testing the variants," and it was evident that the '723
specification and its priority document did not disclose the specifically
claimed thermostable variant. Further:

In this case, to actually possess the variant enzymes claimed in the '723
patent would have required Novozymes to confirm its predictions by actually
making and testing individual variants or at least identifying subclasses of
variants that could be expected to possess the claimed properties, which it did
not do before filing the ['723 priority] application. At best, the ['723
priority] application describes a roadmap for producing candidate alpha-amylase
variants and then determining which might exhibit enhanced thermostability. A
patent, however, "is not a reward for the search, but compensation for its
successful conclusion." Ariad
[Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353 (Fed. Cir.
2010) (en banc)] (quoting University of Rochester, 358 F.3d
at 930 n.10). For that reason, the written description requirement prohibits a
patentee from "leaving it to the . . . industry to complete an unfinished
invention." Id.

Chief
Judge Rader dissented. While his
continued dissatisfaction with the written description requirement was evident
("[a]lthough a separate written description requirement, and the vague
notion of "possession" that it embodies, still troubles me"),
his dissent does not trod that old ground of disagreement with his
brethren. Instead, the Chief Judge
contends that, having established a separate written description requirement it
is a question of fact, and the jury deserves deference to its factual
determinations that should not lightly be overturned by JMOL. On the facts in this case, Chief Judge Rader
finds substantial evidence (including expert testimony, the weight and
persuasiveness of which being particularly within a jury's purview) supporting the jury's
verdict and thus would let it stand:

[T]he jury received expert testimony, heard from skilled protein
engineers, reviewed visual aids and publication excerpts, and examined the
patent document as guided by those skilled in the art, over an eight day trial. The jury was given a special verdict form asking whether DuPont had proven by
clear and convincing evidence that the claims at issue were invalid for lack of
written description. . . . The jury answered in favor of Novozymes, and
substantial evidence supports this determination.